DESCRIPTION (provided by applicant: Chlamydia species provoke serious infections of humans and animals worldwide, despite extensive work to better characterize the biology of infection. Chlamydiae also cause abortions in many domestic animals, and infection by Chlamydia and other microbial pathogens is thought to lead to a large but undetermined fraction of miscarriages and preterm births in humans. Little is known about how Chlamydia infection leads to sterility, and in general, the mechanisms leading to abortion have not been characterized during infection by any microbial pathogen. Recent studies on abortion in model systems in the absence of infection have shown that fetuses are rejected mainly by the innate immune system, via inflammation and complement activation. Secretion of Th2 cytokines at the fetal-maternal interface also favors successful pregnancy, while the pro-inflammatory Thl cytokines, which are required for elimination of chlamydial infection, are harmful to the fetus. Finally, stimulation of CDld-dependent natural killer T (NKT) cells by injection of a CDld ligand induces abortion through a mechanism requiring NKT cell-mediated cytotoxicity and pro-inflammatory cytokines. Our preliminary data show that Chlamydia infection induces abortion in mice, even though the fetus itself is not infected. Chlamydia infection leads to complement activation (C3 deposition) in the uterus of non-pregnant mice, and in the labyrinthine zone of the placenta of pregnant mice. Expression of the NKT cell receptor is weak in the uterus or the placenta of uninfected mice, but increases greatly in the placenta of infected mice. The overall hypothesis to be tested is that the innate immune system, via complement and/or NKT cell activation, could lead to abortion in Chlamydia-infected mice. Our first two goals will be to characterize Chlamydia infection in C3- and CD1d-deficient mice, which have not been studied yet in the absence of pregnancy. We will then characterize the effects of complement activation and NKT cell activation on the outcome of pregnancy during Chlamydia infection.